Cancer is a class of diseases in which a group of cells display the traits of uncontrolled growth (growth and division beyond the normal limits), invasion (intrusion on and destruction of adjacent tissues), and sometimes metastasis (spread to other locations in the body via lymph or blood). Cancer represents one of the leading causes of death in the world.
Cancers can be classified according to the organ, tissue and cell-type from which the cancerous cells originate: lung, colon, liver, skin etc.
Lung cancer is the leading cause of cancer-related deaths throughout the world. Among those, non-small cell lung cancer (NSCLC) represents 80% of the cases. The size of the primary tumor, the invasion of loco-regional nodes and, the presence of distant metastases, determine the survival rate. These parameters are used to define the stage of the disease and to decide the optimal patient management.
In spite of the progress in medical and surgical treatments, long term survival remains poor, with overall values ranging from 20 to 30% at 5 years after surgery. Patients generally relapse within 3 years, with the development of metastases.
Currently available therapies for lung cancer are neo-adjuvant chemotherapy followed by surgery (the chemotherapy being decided if the patient is not operable or presents an invasion of the mediastinal ganglions), or surgery alone. In both cases, the surgical intervention can be followed by chemotherapy in order to eradicate any residual tumor cells.
Novel cancer therapies are being developed which are based on the amplification of the immune response.
Toll-Like Receptors (TLR) are cell-surface or endogenous receptors by which cells recognize Pathogen Associated Molecular Patterns (PAMP) (Killen SD 2006). These receptors are involved in the recognition of molecular patterns, such as single-stranded and double-stranded RNA, double-stranded DNA, LPS, lipoteichoic acid, etc . . . . and are mainly expressed by cells of the immune system.
Immunotherapeutic treatments based on the use of TLR9 ligands are currently being tested for the treatment of solid cancers, such as NSCLC (Kanzler H. et al. 2007 Nature Medicine, 13:532; Krieg A. M. 2007, JCI, 117:1184).
U.S. patent application Ser. No. 11/184,191 to Lebecque et al. describes methods for treating Toll-like receptor expressing cancers and tumor cells by selecting a TLR expressing tumor cell and contacting the cell with a therapeutically effective amount of a TLR ligand. In particular, Ser. No. 11/184,191 describes methods for treating TLR3 expressing cancers and tumors cells using TLR3 agonists. The TLR3 agonist induces apoptosis of the tumor cells expressing TLR3.
Another treatment currently under investigation is the use of TLR7 or 8 agonists as adjuvants to prime the antitumoral immune responses. The lead compound of the imidazoquinoline family, imiquimod, is marketed as a topical formulation for use against primary skin tumors and cutaneous metastasis (Schön & Schön, Oncogene, 2008). In skin cancer, there is relative efficacy which is mainly due to increased immune functions, particularly enhancement of Natural Killer cell antitumor activity, dendritic cell maturation and T cell immunity to tumor antigens (Schön 2008, Kanzler 2007, Stary 2007). In contrast, treatment with a TLR7 agonist does not influence the clinical outcome in metastatic melanoma (Dummer et al., 2008). Research efforts are being made in order to develop other TLR7 agonists for use as immunotherapeutic agents (Wu et al., 2007, PNAS). However, the efficacy of TLR agonists as adjuvants for cancer therapy remains to be established.
There is still an unmet need for predicting the response to treatment of cancer, and for new therapeutic methods for treating cancer, in particular NSCLC.